Overexpression of GYS1, MIF, and MYC Is Associated With Adverse Outcome and Poor Response to Azacitidine in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Falantes, José; Trujillo, Pablo; Piruat, José I.; Calderón, Cristina; Márquez-Malaver, Francisco J.; Martín-Antonio, Beatriz; Millán, Africa; Gómez, Mercedes; González, José; Martino, M.L.; Montero, Isabel; Parody, Rocío; Espigado, Ildefonso; Urbano-Ispizúa, Álvaro; Pérez-Simón, Josè Antonio

doi:10.1016/j.clml.2014.10.003

Cited by 27 publications

(30 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, overexpression of Myc has been reported to be associated with adverse clinical outcome and drug resistance in AML. 37 , 38 However, definitive conclusions about quinacrine being a selective pol-I inhibitor will require further more detailed molecular studies.…”

Section: Discussionmentioning

confidence: 99%

Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

Eriksson

Österroos

Hassan

et al. 2015

Blood Cancer Journal

View full text Add to dashboard Cite

To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC 1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups ( o50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug-drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

Eriksson

Österroos

Hassan

et al. 2015

Blood Cancer Journal

View full text Add to dashboard Cite

show abstract

“…Falantes et al [35] analyzed the expression of genes involved in cell proliferation and glycolytic metabolism on the response to therapy and outcome in 85 patients with MDS or AML receiving azacitidine. Patients with overexpression of glycogen synthase 1 (GYS1), macrophage migration inhibitory factor (MIF), and MYC did not seem to benefit from azacitidine.…”

Section: Prognostic Factors For Epigenetic Therapymentioning

confidence: 99%

Epigenetic therapy of myelodysplastic syndromes and acute myeloid leukemia

Voso

Fianchi

2015

Current Opinion in Oncology

View full text Add to dashboard Cite

show abstract

“…2B). As MIF expression has been shown to be increased in AML patients compared with normal patients (20) and the ability of MIF to induce IL8 production by primary CLL (14), we hypothesized that MIF from AML was responsible for the increased IL8 expression in BM-MSCs. To test this hypothesis, we stimulated BM-MSCs with 100ng/mL recombinant human MIF and assayed for IL8 mRNA and protein expression over a period of 24 hours.…”

Section: Aml-derived Mif Induces Il8 Expression In Bm-mscsmentioning

confidence: 99%

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

et al. 2017

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) cells exhibit a high level of spontaneous apoptosis when cultured in vitro but have a prolonged survival time in vivo, indicating that tissue microenvironment plays a critical role in promoting AML cell survival. In vitro studies have shown that bone marrow mesenchymal stromal cells (BM-MSC) protect AML blasts from spontaneous and chemotherapy-induced apoptosis. Here, we report a novel interaction between AML blasts and BM-MSCs, which benefits AML proliferation and survival. We initially examined the cytokine profile in cultured human AML compared with AML cultured with BM-MSCs and found that macrophage migration inhibitory factor (MIF) was highly expressed by primary AML, and that IL8 was increased in AML/BM-MSC cocultures. Recombinant MIF increased IL8 expression in BMMSCs via its receptor CD74. Moreover, the MIF inhibitor ISO-1 inhibited AML-induced IL8 expression by BM-MSCs as well as BM-MSC-induced AML survival. Protein kinase C b (PKCb) regulated MIF-induced IL8 in BM-MSCs. Finally, targeted IL8 shRNA inhibited BM-MSC-induced AML survival. These results describe a novel, bidirectional, prosurvival mechanism between AML blasts and BM-MSCs. Furthermore, they provide biologic rationale for therapeutic strategies in AML targeting the microenvironment, specifically MIF and IL8.

show abstract

Overexpression of GYS1, MIF, and MYC Is Associated With Adverse Outcome and Poor Response to Azacitidine in Myelodysplastic Syndromes and Acute Myeloid Leukemia

Cited by 27 publications

References 43 publications

Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

Epigenetic therapy of myelodysplastic syndromes and acute myeloid leukemia

MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

Contact Info

Product

Resources

About